public assessment report ukpar imatinib 100 mg film … pharma (uk) limited. par ... the mhra...

Public Assessment Report

UKPAR

Imatinib 100 mg Film-coated Tablets


(Imatinib mesilate)

UK Licence No: PL 36687/0208-0209

Torrent Pharma (UK) Limited.

PAR Imatinib 100 and 400 mg Film-coated Tablets PL 36687/0208-0209

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LAY SUMMARY



(Imatinib mesilate, film-coated tablet, 100 mg or 400mg)

This is a summary of the Public Assessment Report (PAR) for Imatinib 100 mg Film-coated Tablets (PL

36687/0208) and Imatinib 100 mg Film-coated Tablets (PL 36687/0209). It explains how Imatinib 100

mg and 400 mg Film-coated Tablets were assessed and their authorisation recommended, as well as their

conditions of use. It is not intended to provide practical advice on how to use Imatinib 100 mg and 400

mg Film-coated Tablets.

The products will be collectively referred to as Imatinib throughout the remainder of this public

assessment report.

For practical information about using Imatinib patients should read the package leaflet or contact their

doctor or pharmacist.

What is Imatinib and what is it used for?

This medicine is a treatment for adults and children for:

- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells

usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which

certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients

Imatinib is used to treat a late stage of Chronic Myeloid Leukaemia called “blast crisis”. In children and

adolescents however it may be used to treat all stages of the illness.

- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia

is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute

lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named

lymphoblasts) start growing out of control. Imatinib inhibits the growth of these cells.

This medicine is also a treatment for adults for:

- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in

which some blood cells start growing out of control. Imatinib inhibits the growth of these cells in a

certain subtype of these diseases.

- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are

blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib

inhibits the growth of these cells in a certain subtype of these diseases.

- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which

some cells start growing out of control. Imatinib inhibits the growth of these cells.

These applications are the same as Imatinib 100 mg and 400 mg film-coated tablets (PL 17509/0068-

0069) which are already authorised.

The company (Intrapharm Laboratories Limited) that makes Imatinib 100 mg and 400 mg film-coated

tablets (PL 17509/0068-0069) has agreed that its scientific data can be used as a basis for the grant of

identical licences for Imatinib (informed consent).


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How does Imatinib work?

This medicine contains the active ingredient called imatinib mesilate which works by inhibiting the

growth of abnormal cells in the diseases listed above. These include some types of cancer.

How is Imatinib used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of administration is oral

(by mouth).

Use in adults

The patient’s doctor will tell them exactly how many tablets of Imatinib to take.

• If the patient is being treated for CML:

Depending on the patient’s condition the usual starting dose is either 400 mg or 600 mg:

- 400 mg to be taken once a day,

- or 600 mg to be taken once a day.

• If the patient is being treated for GIST:

The starting dose is 400 mg, to be taken once a day.

For CML and GIST, the patient’s doctor may prescribe a higher or lower dose depending on how the

patient responds to the treatment. If the patient’s daily dose is 800 mg, they should take 400 mg in the

morning and 400 mg in the evening.

• If the patient is being treated for Ph-positive ALL:

The starting dose is 600 mg to be taken once a day.

• If the patient is being treated for MDS/MPD:

The starting dose is 400 mg, to be taken once a day.

• If the patient is being treated for HES/CEL:

The starting dose is 100 mg, to be taken once a day. The patient’s doctor may decide to increase

the dose to 400 mg, to be taken once a day, depending on how the patient responds to treatment.

• If you the patient is being treated for DFSP:

The dose is 800 mg per day, to be taken as 400 mg in the morning and 400 mg in the

evening.

Use in children and adolescents

The doctor will tell the child’s carer how many tablets of Imatinib to give to their child. The amount of

Imatinib given will depend on the child’s condition, body weight and height. The total daily dose in

children must not exceed 800 mg with CML and 600 mg with Ph+ ALL. The treatment can either be

given to the child as a once-daily dose or alternatively the daily dose can be split into two

administrations (half in the morning and half in the evening).

When and how to take Imatinib

• Take Imatinib with a meal. This will help protect the patient from stomach problems when

taking Imatinib.

• Swallow the tablets with a large glass of water.

The tablet can be divided into equal doses.

If the patient is unable to swallow the tablets, they can dissolve them in a glass of still water or apple

juice:

• Use about 50 ml for each 100 mg tablet or 200 ml for each 400 mg tablet.

• Stir with a spoon until the tablets have completely dissolved.


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• Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved

tablets may be left behind in the glass.

How long to take Imatinib

The patient must keep taking Imatinib every day for as long as their doctor tells them.

Please read section 3 of the package leaflet for detailed information on dosing recommendations, the

route of administration, and the duration of treatment.

This medicine can only be obtained with a prescription.

For further information on how Imatinib are used, refer to the package leaflet and Summaries of Product

Characteristics available on the Medicines and Healthcare products Regulatory Agency (MHRA)

website.

What benefits of Imatinib have been shown in studies?

Imatinib is considered identical to previously authorised Imatinib 100 mg and 400 mg film-coated

tablets (PL 17509/0068-0069), with the same benefits and risks. So, no new studies have been provided

for Imatinib but reference is made to the studies for Imatinib 100 mg and 400 mg film-coated tablets (PL

17509/0068-0069).

What are the possible side effects from Imatinib?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Imatinib is considered to be identical to the previously authorised applications for Imatinib 100 mg and

400 mg film-coated tablets (PL 17509/0068-0069) with the same benefits and risks.

For a full list of all the side effects reported with Imatinib see section 4 of the package leaflet, available

on the Medicines and Healthcare products Regulatory Agency (MHRA) website.

For the full list of restrictions, see the package leaflet.

Why was Imatinib approved?

The MHRA decided that the benefits of Imatinib are greater than the risks and recommended that they

are approved for use.

What measures are being taken to ensure the safe and effective use of Imatinib?

A Risk Management Plan has been developed to ensure that Imatinib are used as safely as possible.

Based on this plan, safety information has been included in the Summaries of Product Characteristics

and the package leaflet for Imatinib including the appropriate precautions to be followed by healthcare

professionals and patients.

Known side effects are continuously monitored. Furthermore new safety signals reported by

patients/healthcare professionals will be monitored/reviewed continuously.

Other information about Imatinib

Marketing Authorisations were granted in the UK on 27 October 2017.

The full PAR for Imatinib follows this summary.

For more information about treatment with Imatinib read the package leaflet, or contact your doctor or

pharmacist.


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This summary was last updated in November 2017.


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TABLE OF CONTENTS

I Introduction Page 7

II Quality aspects Page 8

III Non-clinical aspects Page 10

IV Clinical aspects Page 10

V User consultation Page 11

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 11

Table of content of the PAR update Page 17


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I INTRODUCTION

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Torrent Pharma (UK) Ltd

Marketing Authorisations for the medicinal products Imatinib (PL 36687/0208-0209) on 27 October

2017. The products are prescription only medicines (POM) indicated for the treatment of:

• paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+)

chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as

the first line of treatment.

• paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in

accelerated phase or blast crisis.

• adult patients with Ph+CML in blast crisis.

• adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute

lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.

• adult patients with relapsed or refractory Ph+ ALL as monotherapy.

• adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with

platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

• adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic

leukaemia (CEL) with FIP1L1-PDGFR rearrangement.

The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.

Imatinib is indicated for

• the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and

adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.

In adult and paediatric patients, the effectiveness of Imatinib is based on overall haematological and

cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic

response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective

response rates in adult patients with unresectable and/or metastatic DFSP. The experience with Imatinib

in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section

5.1). There are no controlled trials demonstrating a clinical benefit or increased survival for these

diseases.

These applications were submitted as simple abridged (informed consent) applications according to

Article 10c of Directive 2001/83/EC, as amended.

The applications cross-refer to the reference products Imatinib 100 mg and 400 mg film-coated tablets

which were first authorised to the marketing authorisation holder (MAH) Intrapharm Laboratories

Limited (PL 17509/0068-0069), on 17 July 2015 via a decentralised procedure (NL/H/3252/001-

002/DC), submitted under article 10(1) of Directive 2001/83/EC, as amended, i.e. as abridged generic

applications, referencing Glivec 100 mg Hard Capsules (EU/1/01/198/002 and EU/1/01/198/006) and

Glivec 400 mg Film-coated Tablets (EU/1/01/198/009, EU/1/01/198/010, EU/1/01/198/013), which are

licenced to Novartis Europharm Limited.

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the

Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor

(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the

colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and

beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation

of these receptor kinases.

No new data were submitted nor were necessary to be submitted for these applications, as the data are

identical to the data for the previously granted cross-referenced products.


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II QUALITY ASPECTS

II.1 Introduction

These are abridged applications for Imatinib (PL 36687/0208-0209) submitted under Article 10c of

Directive 2001/83/EC, as amended.

The applications cross-refer to the reference Imatinib 100 mg and 400 mg film-coated tablets which

were first authorised to the marketing authorisation holder (MAH) Intrapharm Laboratories Limited (PL

17509/0068-0069), on 17 July 2015. The applications are considered valid.

II.2. Drug Substance

Drug substance specifications

The proposed drug substance specifications are consistent with the details registered for the cross-

reference products.

II.3. Medicinal Product

Name

The proposed product names for these applications are Imatinib 100 and 400 mg Film-coated Tablets.

The products have been named in line with current requirements.

Strength, pharmaceutical form, route of administration, container and pack sizes

Each film coated tablet contains 100 mg or 400 mg imatinib (as mesilate). Both strengths of this

medicine are packed into:

• Aluminium/Aluminium blisters. The 100 mg tablet strength is available in pack sizes of 20, 60,

120 or 180 tablets and the 400 mg tablet strength is available in pack sizes of 10, 30 or 90 tablets.

• High-density polyethylene (HDPE) containers. The 100 mg tablet strength is available in a pack

size of 90 tablets and the 400 mg pack size is available in a pack size of 30 tablets.

Not all pack sizes may be marketed.

The proposed shelf life of the unopened product for both presentation types (blisters and containers) is 2

years with no special storage conditions.

The proposed packaging, shelf-life and storage conditions are consistent with the details registered for

the cross-reference product.

Legal status

Prescription only medicine (POM).

Marketing Authorisation Holder/Contact Persons/Company

Torrent Pharma (UK) Ltd, Unit 4, Charlwood Court, County Oak Way, Crawley, West Sussex, RH11

7XA, UK.

The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV has been

provided.

Manufacturers

The proposed manufacturing sites are consistent with those registered for the cross-reference products

and evidence of Good Manufacturing Practice (GMP) compliance has been provided.

Qualitative and quantitative compositions

The proposed compositions are consistent with the details registered for the cross-reference products.


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Manufacturing process

The proposed manufacturing processes are consistent with the details registered for the cross-reference

products and the maximum batch size is stated.

Finished product/shelf-life specifications

The proposed finished product specifications are in line with the details registered for the cross-reference

products.

TSE Compliance

None of the excipients used contain material of animal or human origin.

Bioequivalence

No bioequivalence data are required to support these simple abridged applications because the proposed

products are manufactured to the same formulae utilising the same processes as the cross-reference

products, Imatinib 100 mg and 400 mg film-coated tablets (PL 17509/0068-0069).

Expert Report

The applicant cross-refers to the data for Imatinib 100 mg and 400 mg film-coated tablets (PL

17509/0068-0069) to which these applications are claimed to be identical. This is acceptable.

Product Name and Appearance

See Section II.3 ‘Medicinal Product; Name’ for details of the proposed product names. The appearance

of the products is identical to that of the cross-reference products.

II.4 Discussion on chemical, pharmaceutical and biological aspects

The data submitted with the applications is acceptable. The grant of Marketing Authorisations is

recommended.


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III NON-CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no

new non-clinical data have been supplied and none are required.

Ecotoxicity/environmental risk assessment (ERA)

Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As

the applications are identical versions of already authorised products, it is not expected that

environmental exposure will increase following approval of the Marketing Authorisations for the

proposed products.

Discussion on the non-clinical aspects

The grant of Marketing Authorisations is recommended.

IV CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no

new clinical data have been supplied and none are required.

Risk Management Plan (RMP)

The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), in accordance

with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities

and interventions designed to identify, characterise, prevent or minimise risks relating to Imatinib.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are

listed below:


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Summary table of safety concerns:

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

Discussion on the clinical aspects

The grant of Marketing Authorisations is recommended.

V User consultation

A user consultation with target patient groups on the package information leaflet (PIL) has been

performed on the basis of a bridging report making reference to the PIL Glivec 400 mg film-coated

tablets (Novartis Europharm Limited) for content and Levetiracetam Hetero 750 mg Film-Coated tablets

for layout (hetero Europe, S.L). The bridging report submitted by the applicant is acceptable.

VI Overall conclusion, benefit/risk assessment and recommendation

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. The applicant’s product is identical to the cross-reference product. Extensive clinical

experience with imatinib mesilate is considered to have demonstrated the therapeutic value of the

compound. The benefit/risk balance is, therefore, considered to be positive.


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Summaries of Product Characteristics (SmPC), Patient Information Leaflets (PIL) and Labels

The SmPC and PIL are consistent with the details registered for the cross-reference products.

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for this medicine is presented below:


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Annex 1

Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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